PROJECT SUMMARY/ABSTRACT Recent calls from the President, Surgeon General, and the NIMH-sponsored Suicide Research Prioritization Agenda emphasize a dire need for the identification of biological predictors of acute suicide risk that are amenable to intervention. In response, the proposed experimental work investigates a causal role of perimenstrual (around menses) withdrawal from the hormones estradiol (E2) and progesterone (P4) in previously-documented acute perimenstrual increases in suicidality. The proposed project also fully prepares the candidate for a uniquely impactful research career in the pathophysiology of suicide. The aim of the proposed K99 research is to test the hypothesis that natural perimenstrual E2/P4 withdrawal acutely increases suicidality. Using a placebo-controlled, within-person design in a sample of 30 women with current suicidal ideation but minimal risk for suicide attempt, the experiment will test the hypothesis that suicidality will be heightened during natural perimenstrual E2/P4 withdrawal (under placebo), but that experimental prevention of this perimenstrual E2/P4 withdrawal will prevent these perimenstrual increases in suicidality. The aim of the R00 research will be to disentangle the roles of E2 and P4 withdrawal in perimenstrual worsening of suicidality using an expanded three-arm within-person experiment (perimenstrual E2/P4 withdrawal under placebo, E2 stabilization [with perimenstrual P4 withdrawal], and P4 stabilization [with perimenstrual E2 withdrawal]), also in 30 women with current suicidal ideation but minimal suicide attempt risk. It is predicted that only natural P4 withdrawal conditions will be associated with worsened suicidality, mediated by withdrawal from P4-derived neurosteroids. Both projects will utilize multi-modal measurement (tasks, interviews, phone assessments, and ecological momentary assessment [EMA]). Mentorship: Experts from UNC Chapel Hill and neighboring Duke University will mentor the candidate: Susan Girdler, Ph.D. (mentor) will provide mentorship in hormone manipulation. Mitch Prinstein, Ph.D. (co-mentor) will provide mentorship in suicide and risk management. David Rubinow, M.D. contributes expertise in the neurobiological effects of ovarian hormones. Steven Young, M.D., Ph.D. contributes expertise in manipulation of the menstrual cycle. Daniel Bauer, Ph.D. provides expertise in advanced statistics. M. Zachary Rosenthal, Ph.D. contributes expertise in suicidality and EMA. Career Goal: The candidate is committed to a research career focused on the role of hormone changes in impulsivity and suicidality. Her goal is to contribute knowledge through R01-funded projects while also translating findings into treatments. Career Development: Her previous work has established prospective associations between acute hormone changes and impulsivity (aggression, alcohol abuse); this award will allow her to develop skills to conduct safe experiments that will determine the causal role of hormone change in suicidality. Training Outcomes include skills in hormonal experiments, research-based suicide risk management, ecological momentary assessment, and multimodal measurement of suicide-related constructs.